tbuckley/cabot-search huggingface dataset:
Abstract 4154: mRNA-based immunotherapies to treat women's cancers
Authors: Dan Tse
Journal: Cancer Research (2023)

Abstract With its ability to potentially code for any given protein, peptide and fragments, synthetic mRNA has landed itself a broad range of cancer immunotherapy applications, including costimulatory receptors, therapeutic antibodies, vaccines, and cytokines able to change the tumor microenvironment.We have been able to leverage our mRNA platform to generate a vaccine for HPV-associated cervical cancer (CC), as well as an immune-stimulatory cytokine for triple negative breast cancer (TNBC), both diseases that disproportionately affects minorities who do not participate in routine medical screenings and contribute to disparity in mortality beyond individual risk factors.IL-12 is a potent pro-inflammatory type 1 cytokine with potential to enter the clinical practice as immunotherapy for cancer. Its use in the form of recombinant protein and/or DNA plasmid has been hampered by issues with systemic toxicity or protein bioavailability within the tumor. To overcome these roadblocks, we developed a novel secreted single chain IL-12p70 mRNA. Intra-tumoral dosing of this mRNA induced tumor regression in a syngeneic and orthotopic mouse model of TNBC. Almost all cervical cancers are HPV (human papilloma virus) associated. We have developed a therapeutic vaccine, based on a single mRNA coding for two de-risked antigens, that is able to induce a T cell response against the oncogenic proteins E6 and E7 of the most common serotype (HPV16). When injected intramuscularly in mice bearing C3.43 masses, this vaccine suppressed tumor growth and generated immunological memory.Currently, these women’s cancers do not have a cure or an effective standard of care. With an efficacy that relies on a few injections and non-invasive routes of administration, we believe our innovative RNA-based pharmaceuticals might close some treatment gaps. Citation Format: Dan Tse. mRNA-based immunotherapies to treat women's cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4154.
Abstract 6182: Tumor treating fields (TTFields) concomitant with PARP inhibitors or carboplatin for treatment of ovarian cancer cell lines
Authors: Antonia Martinez-Conde, Hila Ene, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2023)

Abstract Purpose/Objectives: Ovarian cancer continues to be the leading cause of death among gynecological malignancies. Platinum-based chemotherapy is recommended after surgery for most patients with ovarian cancer; and PARP inhibitors (PARPi) are suggested as maintenance therapy. Both therapies induce DNA damage that require the proper activity of the Fanconi Anemia (FA)- BRCA pathway for its resolution, and hence are most beneficial in cancers with a BRCA mutation. However, 75% of patients with ovarian cancer do not harbor BRCA mutations, and thus may experience limited benefit from these treatments. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recently, TTFields have been shown to induce a state of BRCAness in various cancer types, and to be effective in ovarian cancer pre-clinical models. The objective of the current study was to examine the effect of TTFields concomitant with carboplatin or PARPi on ovarian cancer cell lines. Materials/Methods: A2780 (BRCA wild type) and OVCAR3 (BRCA mutated) ovarian carcinoma cells were treated with TTFields (72 h, 1 V/cm RMS, 200 kHz), alone or with concomitant application of carboplatin or the PARP inhibitors olaparib or niraparib. Efficacy was examined via measurements of cell count, colony formation, and induction of apoptosis. The overall effect was calculated by multiplying cell count with colony formation. Results: Application of TTFields to A2780 or OVCAR3 cells resulted in reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib each displayed dose dependent effects in both cell lines, with higher sensitivity demonstrated in the BRCA mutated cells. Concomitant application of TTFields with any of these drugs displayed a synergistic interaction in the BRCA wild type A2780 cells and an additive effect in the BRCA mutant OVCAR-3 cells. Conclusions: The data suggest potential benefits for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even in the absence of background BRCA mutations, in accordance with the BRCAness state induced by TTFields. As such, TTFields may enhance the efficacy of treatment for ovarian cancer in both the adjuvant and maintenance settings. Citation Format: Antonia Martinez-Conde, Hila Ene, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Tumor treating fields (TTFields) concomitant with PARP inhibitors or carboplatin for treatment of ovarian cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6182.
Abstract 3170: Predicting the signals of adverse drug reactions on the basis of medical data
Authors: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim
Journal: Cancer Research (2023)

Abstract Multiple drugs are often prescribed for the better treatment of a disease. While the use of multiple drugs is to improve the overall therapeutic efficacy, it can also lead to unintended adverse drug reactions (ADRs) from drug-drug interactions (DDIs). More than 30% of ADRs have been reported to be caused by DDIs. Because of the importance of DDIs and ADRs, many computational models have been developed to predict DDIs and/or ADRs. However, these computational models mostly make predictions on the basis of molecular features of drugs without considering clinical factors, which consequently does not allow predictions in a person-specific manner. To address this problem, we present a machine learning model that predicts the signals of ADRs potentially caused by DDIs on the basis of medical data. Medical data used for model development come from MIMIC-IV, and include age, ethnicity, gender, patients’ disease information (i.e., ICD-10) and information on drugs administered (e.g., molecular structure and dose). The medical data were subjected to extensive preprocessing based on a domain knowledge, and multiple machine learning methods were examined to predict the ADR signals using the preprocessed dataset. ADR signals are captured by classifying whether each of the selected laboratory measurements (e.g., hematocrit, creatinine, and hemoglobin) is normal. The best-performing model showed the average AUROC of more than 0.8. The machine learning model developed in this study can be useful for examining potential harms when considering multiple drugs, including anticancer drugs. Citation Format: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim. Predicting the signals of adverse drug reactions on the basis of medical data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3170.
Abstract 2146: LDH as a surrogate marker for both pCR and survival in breast cancer patient
Authors: In Hee Lee, Soo Jung Lee, Jeeyeon Lee, Ho Yong Park, Jin Hyang Jung, Nora Jee-Young Park, Ji-Young Park, Yee Soo Chae, Byeongju Kang
Journal: Cancer Research (2023)

Abstract Background: Glucose metabolism in cancer cells produces various glycolytic metabolites, which can affect cancer progression and treatment outcome. Herein we evaluated the association of glucose transporters and enzymes involved in glucose metabolism with clinic-pathological factors and outcomes in breast cancer patients who underwent neoadjuvant chemotherapy(NAC). Methods: We selected 7 target transporters and enzymes(GLUT1, hexokinase 2, lactate dehydrogenase, MCT1, MCT4, IGF1RA, and IGF1RB) involved in glucose metabolism. Their tumoral expressions were scored both quantitively and qualitatively based on tissue microarrays and immunohistochemistry as previously described (Pinheiro et al, 2010) and then evaluated in relationships with pretreatment clinical/pathological characteristics and treatment outcomes including findings of 18F-FDG PET/CT,pathologic complete response(pCR), and relapse in breast cancer(stage IIA-IIIC) patients who underwent anthracycline or taxane-based NAC. Results: Of the 236 enrolled patients, 145(61.4%), 44(18.6%), and 47(19.9%) were luminal, HER2-enriched, and TNBC subtypes. Pathologic CR was determined 50(21.2%) and 57(24.2%) relapses, 42(17.8%) distant relapses, and 28 deaths were observed during median follow-up duration of 64.0 (32.3-114.9) months. The expression rates of the target molecules were 76.0, 31.1, 42.1, 54.9, 67.9, 78.4, and 49.8% for GLUT1, hexokinase 2 (HK2), lactate dehydrogenase(LD), MCT1, MCT4, IGF1RA, and IGF1RB, respectively. Among target molecules in glucose metabolism, LD was significantly associated with pCR(OR=0.251; p-=0.016) and distant disease-free survival (HR= 2.29; P=0.019). Plus, LD expression shows a trend for a high SUVmax of primary tumor 18F-FDG PET/CT(OR=1.797 P=0.060). Conclusion: Tumoral expression of lactate dehydrogenase can be considered as a predictive marker for pCR to NAC and plus prognostic marker for survival in patients with breast cancer. Citation Format: In Hee Lee, Soo Jung Lee, Jeeyeon Lee, Ho Yong Park, Jin Hyang Jung, Nora Jee-Young Park, Ji-Young Park, Yee Soo Chae, Byeongju Kang. LDH as a surrogate marker for both pCR and survival in breast cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2146.
Abstract 5527: Undergraduate cancer research scholars’ community field experiences encourage community engagement to curb future disparities in the cancer workforce
Authors: Melinda Butsch Kovacic, Rachael D. Nolan, Melissa Loyd, Sharon Sauter, Karen Ramos, John R. Kues
Journal: Cancer Research (2023)

Abstract Lack of access to cancer prevention, early screening, and treatment, particularly in low socioeconomic, underserved communities, are cited as substantial barriers to improving survivorship. Overcoming the complexity of this problem will require a larger, diverse, and dedicated workforce. Community engagement can lead to greater awareness of and both access and accrual to research. Encouraging trainees understanding of and participation in community engagement early on is one approach to curb cancer research related disparities. The current pipeline of cancer-focused healthcare professionals and researchers that understand, appropriately engage, and connect with their target communities and patient populations is dangerously inadequate. To expand our future culturally competent, cancer-focused workforce, the University of Cincinnati Cancer Center has established the Cancer Research Scholars Program which is supported in part by a National Cancer Institute R25. The program offers to 20-23 undergraduate scholars each year, unique and inspiring paid research opportunities across the cancer continuum and educational experiences that included cancer topics, professional development, team science, and both cultural humility and microaggression training. Importantly, all scholars prepare for and participate in one of three community-engaged, cancer-focused summer field experiences offered with our community partners to encourage the supporting of and//or active participation in community-engaged research, education, and outreach in their future cancer careers. Twelve of the 23 summer 2022 Scholars were also invited to continue their research into the academic year either in-person or virtually. After year 1, Scholars and mentors completed surveys and on-camera interviews about the program highlighting the program’s successes as well as areas for improvement. Nearly all Scholars appreciated the community engagement opportunities offered and understood their value to their potential careers. Annual tracking of these Scholars will determine the program’s longer-term impact on the cancer workforce. Citation Format: Melinda Butsch Kovacic, Rachael D. Nolan, Melissa Loyd, Sharon Sauter, Karen Ramos, John R. Kues. Undergraduate cancer research scholars’ community field experiences encourage community engagement to curb future disparities in the cancer workforce. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5527.
Abstract 2071: Detecting somatic DNA copy number differences with DiNAMIC.Duo
Authors: Vonn Walter, Hyo Young Choi, Xiaobei Zhao, Yan Gao, Jeremiah Holt, D. Neil Hayes
Journal: Cancer Research (2023)

Abstract Somatic DNA copy number alterations (CNAs) arise in tumor tissue because of underlying genomic instability. Recurrent CNAs that occur in the same genomic region across multiple independent samples are of interest to researchers because they may contain genes that contribute to the cancer phenotype. However, differences in copy number states between cancers are also commonly of interest, for example when comparing tumors with distinct morphologies in the same anatomic location. Current methodologies are limited by their inability to perform direct comparisons of CNAs between tumor cohorts, and thus they cannot formally assess the statistical significance of observed copy number differences or identify regions of the genome where these differences occur. We introduce the DiNAMIC.Duo R package that can be used to identify recurrent CNAs in a single cohort or recurrent copy number differences between two cohorts, including when neither cohort is copy neutral. The TCGA studies of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) identified statistically significant CNAs in many known cancer-related genes, including gains of EGFR and losses of CDKN2A in each tumor type separately. By directly comparing the two cohorts, DiNAMIC.Duo detects statistically significant copy number differences for CDKN2A, thus suggesting that losses are more pronounced in LUSC; in contrast, differences for EGFR are not statistically significant, which suggests similar levels of gain. Existing methods that detect recurrent CNAs in a single cohort cannot make this distinction. Recent studies have leveraged TCGA data to find known cancer genes in chr3q, chr14q13, and chr20q11 that are differentially expressed in LUAD vs. LUSC. DiNAMIC.Duo identifies statistically significant copy number differences in these regions, which suggests that the observed expression changes may be driven by underlying differences in copy number. Citation Format: Vonn Walter, Hyo Young Choi, Xiaobei Zhao, Yan Gao, Jeremiah Holt, D. Neil Hayes. Detecting somatic DNA copy number differences with DiNAMIC.Duo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2071.
Abstract 932: Snapshot! Exploring sample diversity of sarcoma cancers across common data repositories
Authors: Alfredo Enrique Gonzalez, Yash Patel, Chenghao Zhu, Takafumi N. Yamaguchi, Mao Tian, Sarah Hiyari, Ahmad A. Shihabi, Stefan Eng, Helena Winata, Jaron Arbert, Arpi Beshlikyan, Ardalan Davarifar, Alice Soragni, Paul C. Boutros
Journal: Cancer Research (2023)

Abstract Sarcoma is a cancer which originates in the body's connective tissues of mesenchymal origin. These are tissues like bones and muscles that support or protect other parts of the body. About ~16,000 sarcomas are diagnosed annually in the US, with ~6,700 deaths attributed to the disease. Sarcomas are typically divided into two major groups: bone sarcomas and soft-tissue sarcomas, each of which has multiple subtypes. However, because of their diversity in site-of-origin, sarcomas vary greatly in their presentation and histological features. Based on The World Health Organization’s (WHO) current classification system that categorizes musculoskeletal soft tissue tumours (STT) and bone tissue tumours, there are 50+ subtypes of sarcoma recognized today. Unsurprisingly, given the relative rarity of sarcoma type tumors, sample procurement has proved a challenge for the field. Consequently, there currently exist major gaps in our understanding of the genetic and molecular hallmarks of various sarcoma subtypes. Here we examine the sample and subtype classifications of sarcoma across some of the major DNA sequencing studies and data repositories to provide an overview of the available sample space. We highlight areas where the sample procurement is lagging and discuss subtypes that are missing all-together. Inclusion of some of the major genomic correlates showcases some of the similarities shared by these sequencing efforts, while emphasizing key genetic differences between subtypes. This work provides a clear roadmap for clinicians on how to best prioritize future sarcoma sample procurement and sequencing. Citation Format: Alfredo Enrique Gonzalez, Yash Patel, Chenghao Zhu, Takafumi N. Yamaguchi, Mao Tian, Sarah Hiyari, Ahmad A. Shihabi, Stefan Eng, Helena Winata, Jaron Arbert, Arpi Beshlikyan, Ardalan Davarifar, Alice Soragni, Paul C. Boutros. Snapshot! Exploring sample diversity of sarcoma cancers across common data repositories [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 932.
Abstract 2148: Robust detection of somatic genetic alterations in pancreatic cancer ascites
Authors: Rajya L. Kappagantula, Alvin P. Makohon-Moore, Shigeaki Umeda, Elias-Ramzey R. Karnoub, Jerry P. Melchor, Laura D. Wood, Christine A. Iacobuzio-Donahue
Journal: Cancer Research (2023)

Abstract Introduction: Regardless of the stage at diagnosis most patients with pancreatic ductal adenocarcinoma develop peritoneal disease and some malignant ascites (MA) as well. Prior studies have shown that MA negatively affects overall treatment efficacy and survival. Despite the clinical significance of MA it has not been studied to any great extent. Methods: We collected MA and matched normal tissue samples at autopsy from 20 PDAC patients who were initially diagnosed at stages IIB to IV. Whole exome or targeted sequencing was previously performed on each PDAC. Each MA sample was centrifuged twice at 4000 RPM first and then at 15000 RPM to separate the cell pellet (CP) from the cell-free ascites fluid. We next extracted DNA from the CP, matched normal tissue, and the cell-free DNA (cfDNA) from the ascites fluid, and all were submitted to the Genomics Core for MSK-IMPACT, a targeted cancer gene panel representing 505 genes. Results: Results of the first five patients are complete and the remaining are in process. Comparison of the CPs and/or cfDNA to the matched tumor samples indicated 100% concordance for detected variants. However, the somatic alterations of the CP specifically versus the matched cfDNA were divergent in all patients analyzed thus far. Virtually all copy number alterations in all patients were deep deletions (range 66 to 187 cancer genes deleted) affecting multiple DNA repair pathways including homologous recombination deficiency and microsatellite repair. Conclusions: Samples of MA, when both the cell pellet and cfDNA are sequenced, accurately represent the genetic features of the matched PDAC tissue and may serve as an alternative mode of sampling for precision medicine. Differences in the genetics of the CP versus the cfDNA suggest polyclonality in the peritoneal space. Moreover, the finding of deep deletions in targetable DNA repair pathways suggest a therapeutic vulnerability for exploration. Given that paracentesis is often performed in the palliative setting and may be performed multiple times over the course of a patients’ management, it also offers an opportunity to determine how clonal dynamics in the peritoneal space change over time. Patients with MA have poor overall survival compared to patients without MA so these patients may benefit from this type of tracking which could potentially help with their treatment. Citation Format: Rajya L. Kappagantula, Alvin P. Makohon-Moore, Shigeaki Umeda, Elias-Ramzey R. Karnoub, Jerry P. Melchor, Laura D. Wood, Christine A. Iacobuzio-Donahue. Robust detection of somatic genetic alterations in pancreatic cancer ascites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2148.
Abstract 439: From foe to friend: <i>In vivo</i> reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating <i>N</i>-myristoyltransferase activity
Authors: Wouter W. Kallemeijn, Sarah Spear, Josephine Walton, Claudio Bussi, Christelle Soudy, Helen R. Flynn, Mark Skehel, David Carling, Roberto Solari, Iain A. McNeish, Edward W. Tate
Journal: Cancer Research (2023)

Abstract Tumor-associated macrophages (TAMs) play a central role in cancer by driving tumor growth, metastasis, therapy failure and cancer recurrence. Macrophage plasticity and diversity allows classification along a M1-M2 polarization axis, where TAMs have a M2-like polarization, associated with a pro-tumoral phenotype, whereas M1 macrophages exhibit anti-tumor functions. Reprogramming TAMs to a M1-like anti-cancer phenotype is an increasingly coveted therapeutic strategy in oncology. Here, we report TAMs can be favorably reprogrammed by modulating N-myristoyltransferase (NMT) activity using on-target, drug-like inhibitors (NMTi). We identified &amp;gt;100 N-myristoylated proteins differentially expressed by macrophages along the M1-M2 polarization axis. In TAM-like M2 macrophages, 42 N-myristoylated proteins exhibited higher NMTi sensitivity as compared to other polarizations, and these NMT substrates significantly enriched in anti-inflammatory, immunity- and metabolism-related pathways. Unique to TAM-like M2 macrophages, NMT modulation by NMTi induces significant transcriptomic and proteomic changes, effectively switching the polarization towards a M1-like anti-cancer phenotype that is characterized by a M1-like spindle morphology, a M1-like glycolytic state, and induction of a pro-inflammatory secretome exhibiting potent anti-tumoral activity towards ovarian cancer spheroids in vitro. In vivo proof-of-principle was established in the syngeneic, macrophage-driven ID8 mouse model for human ovarian cancer, where NMTi treatment significantly reprogrammed murine M2-like TAMs into a M1-like anti-cancer phenotype, concomitantly reducing tumor burden without observable side-effects, and significantly extending median survival by 16 days. We are currently further investigating the intricacies that N-myristoylation plays in macrophage polarization, as well as further establishing the scope of NMTi-driven in vivo reprogramming of TAMs beyond ovarian cancer. Citation Format: Wouter W. Kallemeijn, Sarah Spear, Josephine Walton, Claudio Bussi, Christelle Soudy, Helen R. Flynn, Mark Skehel, David Carling, Roberto Solari, Iain A. McNeish, Edward W. Tate. From foe to friend: In vivo reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 439.